The central hypothesis of this proposal is that expansion of trinucleotide repeats in genes expressed in the brain may be one of the etiologies of neuropsychiatric disorders, including manic depressive illness. Expansion of trinucleotide repeats (CTC or CGG) in these genes has recently been discovered to underlie three different disorders (Fragile X Syndrome, Kennedy's disease, and myotonic dystrophy). The pleiotropic manifestations and unusual pattern of inheritance of these latter disorders are reminiscent of some pedigrees of manic depressive illness, schizophrenia, and other disorders, suggesting that at least some subtypes of these illnesses could be caused by a similar mechanism. We have preliminary data showing that there are many additional novel trinucleotide repeat containing genes expensed in the human brain. In Specific Aims #1 and 2 we will clone cDNAs for new human genes with CGG and CTG repeats, and characterize these cDNAs by sequencing them and by analyzing the expression of their mRNAs. In Specific Aim #3 we will determine their chromosomal localizations by doing PCR using human chromosome specific mouse human hybrid cell lines. We will analyze the lengths of the repeats using PCR in the Centre d'Etude du Polymorphisme Humain (CEPH) parents to determine their distribution in a well characterized population background. Based on the preliminary data, we predict that the lengths of these repeats will frequently be polymorphic. Those that are highly polymorphic will be mapped in the CEPH pedigrees and entered into the human genetic linkage map. In Specific Aim #4, we will search for expansions of the repeats in these novel genes in patients with manic depressive illness, as well as schizophrenia, autism, and mental retardation, in collaboration with ongoing fly study investigations at Johns Hopkins. For all genes, we will analyze all the probands in the initial screen using PCR. In addition, for the strongest candidate genes, we will study three affected and three unaffected members (including the parents) of each unilineal pedigree. If there appears to be expansion of the repeats in affected members, we will then analyze the entire pedigree as well as other pedigree.s in detail using PCR and genomic Southern blots. We predict that we will find one or more genes whose trinucleotide repeats are expanded only in affected members and therefore will be genes involved in those forms of manic depressive illness or other neuropsychiatric disorders.